OnE hundred years have passed since Felix
Hoffman, working at Bayer Industries, reported
the successful synthesis of acetylsalicylic
acid as the first nonsteroidal antiinflammatory
drug (NSAID). [1,2]
At the suggestion of Hermann
Dreser, Bayer’s chief pharmacologist at the time, [3]
the compound was called “aspirin” and was purported
to represent a convenient mechanism for the delivery
of salicylic acid in the treatment of rheumatic diseases,
menstrual pain, and fever. [2] Approximately 40 years
elapsed before Douthwaite and Lintott [4] provided
endoscopic evidence that aspirin could cause gastric
mucosal damage. Numerous reports have corroborated
this observation, [5-8] and the introduction of more
potent agents with an even greater propensity for
toxic effects has increased the awareness of NSAID-induced
gastroduodenal ulcer and provided impetus
for the development of effective NSAIDs with a more
favorable safety profile.

Starting in the early 1970s, numerous new NSAIDs
were developed that were initially believed to be devoid
of gastrointestinal toxicity, but few, if any, are
entirely harmless. These agents constitute one of the
most widely used classes of drugs, with more than
70 million prescriptions and more than 30 billion
over-the-counter tablets sold annually in the United
States. [9] Although NSAIDs are generally well tolerated,
adverse gastrointestinal events occur in a small
but important percentage of patients, resulting in
substantial morbidity and mortality.

EPIDEMIOLOGY OF GASTROINTESTINAL COMPLICATIONS

Because of the broad and nonspecific definitions
of gastrointestinal disorders caused by the use of
NSAIDs, as well as differences in patient populations,
drugs, dosages, and periods of use, estimates of the
prevalence of adverse effects vary greatly. In general,
at least 10 to 20 percent of patients have dyspepsia
while taking an NSAID, although the prevalence
may range from 5 to 50 percent. [10, 11] Within a six-month
period of treatment, 5 to 15 percent of patients
with rheumatoid arthritis can be expected to
discontinue NSAID therapy because of dyspepsia. [11]
According to prospective data from the Arthritis,
Rheumatism, and Aging Medical Information System
(ARAMIS), 13 of every 1000 patients with
rheumatoid arthritis who take NSAIDs for one year
have a serious gastrointestinal complication. The risk
in patients with osteoarthritis is somewhat lower
(7.3 per 1000 patients per year). [12]
The rate of NSAID-related serious gastrointestinal
complications requiring hospitalization has decreased
in recent years. The decrease may be due, at least in
part, to extensive medical-education campaigns that
have persuaded physicians to use newer, less toxic
NSAIDs and non-NSAID analgesics in populations
at high risk. [12] The mortality rate among patients who are hospitalized
for NSAID-induced upper gastrointestinal
bleeding is about 5 to 10 percent. [13]

RISK FACTORS FOR GASTROINTESTINAL COMPLICATIONS

Because dyspeptic symptoms are not a reliable warning
sign, it is important to identify factors that increase
the risk of serious gastrointestinal complications
and to determine methods for reducing this
risk. A number of studies have been designed to
identify patients who are most likely to have adverse
effects of NSAID therapy (Table 1).

Advanced age has been consistently found to be a
primary risk factor for adverse gastrointestinal events.
The risk increases linearly with age. [15-20] Although
previous reports suggested that the risk diminishes
over time, a recent study indicates that the risk of
NSAID-associated gastrointestinal hemorrhage remains
constant over an extended period of observation. [12]
Other risk factors that have been identified in
multiple studies are higher doses of NSAIDs (including
the use of two or more NSAIDs), a history
of gastroduodenal ulcer or gastrointestinal bleeding,
concomitant use of corticosteroids, serious coexisting
conditions, and concomitant use of anticoagulants. [20-27]

However, many of these studies are based
on univariate analysis and do not consider the interactions
among multiple factors and coexisting conditions.
The identification of Helicobacter pylori infection
as a factor in the development of peptic ulcer has
raised the question of a possible synergistic relation
between the presence of H. pylori infection and
NSAID use. Although several studies [29-32] have found
these two factors to be independent, two prospective
studies have suggested a synergistic relation. Bianchi
Porro et al. [33] used the combination of amoxicillin
and omeprazole to treat NSAID users infected with
H. pylori. They found that the eradication of
H. pylori did not affect the rate of ulcer healing.
However, six months after the end of combination
therapy, the cumulative rate of recurrent ulcers was
31 percent among the patients in whom H. pylori
had been eradicated and 46 percent among those
who were still infected. This difference was not statistically
significant.

Chan et al. [34] found that the use of a regimen that
included bismuth subcitrate to eradicate
H. pylori significantly decreased the rate of ulcer development
associated with the use of naproxen. In this study,
gastroduodenal ulcers developed in 26 percent of
H. pylori–infected persons, but in only 7 percent of
those in whom the organism had been eradicated.
The inclusion of bismuth in the drug regimen, however,
makes the findings somewhat ambiguous, because
bismuth can accumulate in the gastric mucosa
and stimulate prostaglandin synthesis. [28]
Most recently, Hawkey et al. [35] randomly assigned 285 patients
with current ulcers or a history of ulcers who were
using NSAIDs to combined treatment with omeprazole,
clarithromycin, and amoxicillin or to treatment
with omeprazole alone. They found that the eradication
of H. pylori did not affect the rate of recurrent
ulcer; in addition, ulcer healing was impaired
even in the patients who were successfully treated
with antibiotics for H. pylori infection. It thus appears
that infection with H. pylori increases the risk
of gastroduodenal mucosal injury associated with
NSAID use only minimally, if at all. [28]

Singh et al. [36] recently proposed a simple, pointbased
algorithm that patients and their physicians
can use to estimate the risk of an NSAID-related
gastrointestinal complication. If confirmed by other
investigators, this tool may help guide decisions about
prescriptions for specific NSAIDs, the use of prophylactic
agents, and the need for and frequency of patient
monitoring. [36]

PATHOGENESIS OF NSAID-INDUCED GASTRODUODENAL MUCOSAL INJURY

Gastroduodenal mucosal injury develops when the
deleterious effect of gastric acid overwhelms the normal
defensive properties of the mucosa. Concepts
about NSAID-induced gastroduodenal mucosal injury
have evolved from a simple notion of topical injury
to theories involving multiple mechanisms with both
local and systemic effects (Fig. 2). The systemic effects
are largely the result of the inhibition of endogenous
prostaglandin synthesis. [37]

Prostaglandin inhibition, in turn, leads to decreases in epithelial mucus, secretion
of bicarbonate, mucosal blood flow, epithelial proliferation,
and mucosal resistance to injury. [38,39] The impairment
in mucosal resistance permits injury by endogenous
factors, including acid, pepsin, and bile
salts, as well as by exogenous factors such as NSAIDs
and possibly ethanol and other noxious agents.

Topical Injury

Mucosal injury is initiated topically by the acidic
properties of aspirin and many other NSAIDs. Because
of a low dissociation constant, which varies according
to the particular agent, these weak acids
remain in their nonionized lipophilic form in the highly
acidic gastric lumen. Such conditions favor migration
through the gastric mucus across plasma membranes
and into surface epithelial cells, where NSAIDs
are dissociated into the ionized form, resulting in
trapping of hydrogen ions. [37] NSAIDs can also cause
topical mucosal damage by diminishing the hydrophobicity
of gastric mucus, thereby allowing endogenous
gastric acid and pepsin to injure the surface
epithelium. [39] In addition, topical mucosal injury may
occur as a result of indirect mechanisms, mediated
through the biliary excretion and subsequent duodenogastric
reflux of active NSAID metabolites. [40,41] For example, although sulindac is administered as a nontoxic
prodrug, its active metabolite, sulindac sulfide,
is excreted into the bile. On entry into the duodenum,
sulindac sulfide causes topical injury to the mucosa
by virtue of its acidic properties.

The Role of Prostaglandins

Topical injury caused by NSAIDs contributes to
the development of gastroduodenal mucosal injury.
However, the systemic effects of these agents appear
to have the predominant role, [37,42,43] largely through
the decreased synthesis of mucosal prostaglandins. [44]
The use of enteric-coated aspirin preparations [44] and
parenteral [45] or rectal [46] administration of NSAIDs in
order to prevent topical mucosal injury has also failed
to prevent the development of ulcers. Moreover,
doses of aspirin as low as 30 mg are sufficient to suppress
prostaglandin synthesis in the gastric mucosa. [47] Prostaglandins are derived from arachidonic acid,
which originates from cell-membrane phospholipids
through the action of phospholipase A-2 (Fig. 3). The
metabolism of arachidonic acid to prostaglandins
and leukotrienes is catalyzed by the cyclooxygenase
pathway and the 5-lipoxygenase pathway, respectively. [1,37] Two related but unique isoforms of cyclooxygenase,
designated cyclooxygenase-1 and cyclooxygenase-2, have been demonstrated in mammalian cells. [48,49]
Despite their structural similarities, they are
encoded by distinct genes and differ with regard to
their distribution and expression in tissues. [50,51]

The cyclooxygenase-1 gene contains a promoter region
without a TATA sequence and is primarily expressed
constitutively. In contrast, the cyclooxygenase-2 gene
is thought to be the inducible form that is nearly undetectable
in most (but not all) tissues under normal
physiologic conditions. Cyclooxygenase-1 appears to function as a “housekeeping”
enzyme in most tissues, including the gastric
mucosa, the kidneys, and the platelets, whereas
the expression of cyclooxygenase-2 can be induced by inflammatory stimuli and mitogens in many different
types of tissue, including macrophages and
synovial cells. [43] It has thus been suggested that the
antiinflammatory properties of NSAIDs are mediated
through the inhibition of cyclooxygenase-2, whereas
adverse effects, such as gastroduodenal ulceration,
occur as a result of effects on the constitutively expressed
cyclooxygenase-1. [43,49] As discussed below, current
strategies for developing NSAIDs with an improved
safety profile include the selective inhibition
of cyclooxygenase-2, with the sparing of cyclooxygenase-1.
Although there is substantial evidence that the suppression
of gastric prostaglandins is the fundamental
mechanism responsible for the gastrointestinal toxicity
of NSAIDs, some studies suggest that other mechanisms
may be involved. For example, ulcers do not
develop spontaneously in mice with a disrupted cyclooxygenase-
1 gene, [52] and Wallace et al. [53,54] reported
that NSAID-induced injury occurred in association
with enhanced adherence of neutrophils to the gastric
vascular endothelium, as the result of an increase in
the expression of intercellular adhesion molecule 1 in
the basal endothelium. [55-58] Neutrophil adherence,
in turn, causes mucosal injury through the release of
oxygen-derived free radicals and proteases. [1]

CLINICAL SPECTRUM OF INJURY

In the majority of patients, NSAID-induced gastroduodenal
mucosal injury is superficial and self-limited.
However, peptic ulcers develop in some patients,
and they may lead to gastroduodenal hemorrhage, perforation,
and death. Serious complications of NSAID
use that are less commonly recognized include pill
esophagitis, small-bowel ulceration, small-bowel strictures,
colonic strictures, diverticular disease, and exacerbations
of inflammatory bowel disease. [9]

The spectrum of NSAID-related gastroduodenal
injury includes a combination of subepithelial hemorrhages,
erosions, and ulcerations that is often referred
to as NSAID gastropathy. The distinction between
erosions and ulcerations depends on pathological definitions,
with ulcers defined as lesions that penetrate
to the level of the submucosa and erosions defined
as lesions confined to the mucosa. For practical
purposes, an endoscopic definition is used, which is
based on a subjective assessment of the size, shape,
and depth of the lesion. Erosions are likely to be
small and superficial, whereas ulcers tend to be larger
(more than 5 mm in diameter) and deeper. [9]

After ingestion of an NSAID, ultrastructural damage
to the gastric surface epithelium occurs within
minutes, and gross, endoscopically detectable hemorrhages
and erosions in the gastroduodenal epithelium
occur within several hours. [59] However, mucosal
adaptation appears to occur in response to long-term
administration of aspirin in most persons. [60, 61] No
area of the stomach is resistant to NSAID-induced
mucosal injury; the most frequently and severely
affected site is the gastric antrum. [59] Although the
prevalence and severity of acute injury vary according
to the drug formulation, [62-64] the acute injury
commonly observed during short-term administration
of NSAIDs is not closely correlated with the
subsequent development of the more clinically relevant
process of mucosal ulceration [20, 21, 65, 66] or with
serious complications. [10, 67, 68] Duodenal mucosal injury
occurs less commonly than gastric damage; however,
ulcer complications associated with NSAIDs occur
with nearly equal frequency in these two sites. [51, 66]
Prospective, cross-sectional endoscopic studies have
shown that the combined prevalence of gastric and
duodenal ulcers is 10 to 25 percent in patients with
chronic arthritis treated with NSAIDs, [10, 67] which is
5 to 15 times the expected prevalence in an agematched
healthy population.